While autologous saphenous vein is the best conduit for peripheral arterial reconstruction, 30% of patients do not have this option due to prior vein harvest, trauma or phlebitis (Sayers et al., “Long-term Results of Femorotibial Bypass with Vein or Polytetrafluoroethylene,” Br. J. Surg. 85:934-8 (1998)). Synthetic grafts made of expanded polytetrafluoroethylene (ePTFE) have been used as substitutes but have low patencies in vessels with diameters less than 6 mm because of early thrombosis or late graft failure from neointimal hyperplasia (Brewster et al., “Factors Affecting Patency of Femorotibial Bypass Grafts,” Surg. Gynecol. Obstet. 157:437-42 (1983)). Infrapopliteal ePTFE grafts have primary patency rates at 4 years as low as 12% (Eagleton et al., “Femoral-Infrapopliteal Bypass With Prosthetic Grafts,” Surgery 126:759-65 (1999)).
Restenosis after percutaneous transluminal angioplasty (PTA) is a multifactorial response to local injury involving elastic recoil, negative arterial remodeling and neointimal formation. Stent technologies help to overcome elastic recoil and negative arterial remodeling associated with vessel injury, but there continues to be a 20-50% rate of restenosis because the continuing pressure exerted by stents against the vessel wall stimulates an increased arterial proliferative response (Beyar, “Novel Approaches to Reduce Restenosis,” Ann. NY Acad. Sci. 1015:367-78 (2004)). One approach to combat neointimal hyperplasia utilizes elution of drugs with antiproliferative properties at the site of vessel injury. Coronary stents that elute rapamycin at the site of angioplasty have reduced neointimal hyperplasia as evidenced by decreased incidence of major adverse coronary events (MACE) and by reduction in binary restenosis, defined as a >50% diameter stenosis of the target lesion (Sousa et al., “Sustained Suppression of Neointimal Proliferation by Sirolimus-eluting Stents: One-year Angiographic and Intravascular Ultrasound Follow-up,” Circulation 104:2007-11 (2001); Morice et al., “A Randomized Comparison of a Sirolimus-eluting Stent with a Standard Stent for Coronary Revascularization,” N Engl. J. Med. 346:1773-80 (2002); Moses et al., “Sirolimus-eluting Stents Versus Standard Stents in Patients with Stenosis in a Native Coronary Artery,” N Engl. J. Med. 349:1315-23 (2003); Holmes et al., “Analysis of 1-year Clinical Outcomes in the SIRIUS Trial: A Randomized Trial of a Sirolimus-Eluting Stent Versus a Standard Stent in Patients at High Risk for Coronary Restenosis,” Circulation 109:634-40 (2004)). Stents have not performed as favorably in the infrainguinal circulation.
ePTFE is able to withstand the biomechanical forces that are exerted on it in the peripheral circulation without structural damage such as fractures that have been reported when stents are placed in the superficial femoral artery (Allie et al., “Nitinol Stent Fractures in the SFA,” Endovasc. Today 3:22-34 (2004)). Non-textile ePTFE grafts are manufactured by an expansion process which transforms an initial full-density PTFE matrix into a structure composed of PTFE nodes interconnected by fine fibrils, which allow tissue ingrowth. The resulting expanded tube contains approximately 15% pure PTFE and 85% air by volume. The PTFE polymer is for the most part chemically inert; moreover, the grafts exhibit little tendency to dilate, have a strong electronegative luminal charge, and are hydrophobic until wetted by body fluids (Cannon, “The Expanded Reinforced Polytetrafluoroethylene Prosthetic Vascular Graft (ERPTFEVG),” In: Vascular Grafting (Wright et al., eds.), Boston, Bristol, London: John Wright—PSG Inc. (1983) at pp. 31-42). Coating ePTFE should not change the handling characteristics of the prosthetic because poor healing, inflammation and thrombosis may result.
Lacking from the prior art is an approach for coating ePTFE or other polymer grafts with a composition that will allow for delivery of one or more therapeutic agents to the graft site, which can thereby decrease neointimal hyperplasia by reducing tissue ingrowth and preserving anastomotic diameter.
The present invention is directed to achieving these objectives and overcoming the above-identified deficiencies in the art.